Could Aspirin Help Prevent Cell Death in Alzheimer’s and Other Neurodegenerative Diseases?

A breakdown product of aspirin blocks cell death associated with Alzheimer’s, Parkinson’s and Huntington’s disease.

A new study finds that a component of aspirin binds to an enzyme called GAPDH, which is believed to play a major role in neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases.

Researchers at the Boyce Thompson Institute and John Hopkins University discovered that salicylic acid, the primary breakdown product of aspirin, binds to GAPDH, thereby stopping it from moving into a cell’s nucleus, where it can trigger the cell’s death. The study, which appears in the journal PLOS ONE, also suggests that derivatives of salicylic acid may hold promise for treating multiple neurodegenerative diseases.

Senior author Daniel Klessig, a professor at Boyce Thompson Institute and Cornell University, has studied the actions of salicylic acid for many years, but primarily in plants. Salicylic acid is the critical hormone for regulating the plant immune system. Previous studies have identified several targets in plants that are affected by salicylic acid, and many of these targets have equivalents in humans.

In the new study, the researchers performed high-throughput screens to identify proteins in the human body that bind to salicylic acid. GAPDH (Glyceraldehyde 3-Phosphate Dehydrogenase) is a central enzyme in glucose metabolism, but plays additional roles in the cell. Under oxidative stress–an excess of free radicals and other reactive compounds–GAPDH is modified and then enters the nucleus of neurons, where it enhances protein turnover, leading to cell death.

The anti-Parkinson’s drug deprenyl blocks GAPDH’s entry into the nucleus and the resulting cell death. The researchers discovered that salicylic acid also is effective at stopping GAPDH from moving into the nucleus, thus preventing the cell from dying.

“The enzyme GAPDH, long thought to function solely in glucose metabolism, is now known to participate in intracellular signaling,” said co-author Solomon Snyder, professor of neuroscience at Johns Hopkins University in Baltimore. “The new study establishes that GAPDH is a target for salicylate drugs related to aspirin, and hence may be relevant to the therapeutic actions of such drugs.”

Furthermore, they found that a natural derivative of salicylic acid from the Chinese medical herb licorice and a lab-synthesized derivative bind to GAPDH more tightly than salicylic acid. Both are more effective than salicylic acid at blocking GAPDH’s movement into the nucleus and the resulting cell death.

Image shows aspirin pills.

Derivatives of aspirin may yield new treatments for neurodegenerative diseases. Credit: Patricia Waldron.

Earlier this year, Klessig’s group identified another novel target of salicylic acid called HMGB1 (High Mobility Group Box 1), which causes inflammation and is associated with several diseases, including arthritis, lupus, sepsis, atherosclerosis and certain cancers. Low levels of salicylic acid block these pro-inflammatory activities, and the above mentioned salicylic acid derivatives are 40 to 70 times more potent than salicylic acid at inhibiting these pro-inflammatory activities.

“A better understanding of how salicylic acid and its derivatives regulate the activities of GAPDH and HMGB1, coupled with the discovery of much more potent synthetic and natural derivatives of salicylic acid, provide great promise for the development of new and better salicylic acid-based treatments of a wide variety of prevalent, devastating diseases,” said Klessig.

About this neurology research

Funding: Research reported in this news release was supported by the U.S. National Science Foundation (IOS-0820405) and the U.S. Public Health Service (MH18501).

Source: Patricia Waldron – Boyce Thompson Institute
Image Source: The image is credited to Patricia Waldron
Original Research: Full open access research for “Human GAPDH Is a Target of Aspirin’s Primary Metabolite Salicylic Acid and Its Derivatives” by Hyong Woo Choi, Miaoying Tian, Murli Manohar, Maged M. Harraz, Sang-Wook Park, Frank C. Schroeder, Solomon H. Snyder, and Daniel F. Klessig in PLOS ONE. Published online November 25 2015 doi:10.1371/journal.pone.0143447


Abstract

Human GAPDH Is a Target of Aspirin’s Primary Metabolite Salicylic Acid and Its Derivatives

The plant hormone salicylic acid (SA) controls several physiological processes and is a key regulator of multiple levels of plant immunity. To decipher the mechanisms through which SA’s multiple physiological effects are mediated, particularly in immunity, two high-throughput screens were developed to identify SA-binding proteins (SABPs). Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) from plants (Arabidopsis thaliana) was identified in these screens. Similar screens and subsequent analyses using SA analogs, in conjunction with either a photoaffinity labeling technique or surface plasmon resonance-based technology, established that human GAPDH (HsGAPDH) also binds SA. In addition to its central role in glycolysis, HsGAPDH participates in several pathological processes, including viral replication and neuronal cell death. The anti-Parkinson’s drug deprenyl has been shown to suppress nuclear translocation of HsGAPDH, an early step in cell death and the resulting cell death induced by the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine. Here, we demonstrate that SA, which is the primary metabolite of aspirin (acetyl SA) and is likely responsible for many of its pharmacological effects, also suppresses nuclear translocation of HsGAPDH and cell death. Analysis of two synthetic SA derivatives and two classes of compounds from the Chinese medicinal herb Glycyrrhiza foetida (licorice), glycyrrhizin and the SA-derivatives amorfrutins, revealed that they not only appear to bind HsGAPDH more tightly than SA, but also exhibit a greater ability to suppress translocation of HsGAPDH to the nucleus and cell death.

“Human GAPDH Is a Target of Aspirin’s Primary Metabolite Salicylic Acid and Its Derivatives” by Hyong Woo Choi, Miaoying Tian, Murli Manohar, Maged M. Harraz, Sang-Wook Park, Frank C. Schroeder, Solomon H. Snyder, and Daniel F. Klessig in PLOS ONE. Published online November 25 2015 doi:10.1371/journal.pone.0143447

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